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Examination of aperture layout designs for an adaptive-stationary multi-pinhole brain-dedicated SPECT system
No full textBackground: Organ specific multi-pinhole (MPH) SPECT imaging could potentially improve the sensitivity/resolution trade-off and image quality (IQ), while facilitating the use of a variety of imaging-agents, thereby addressing diagnostic, quantitative, and research clinical needs.
Purpose: Investigate through simulation six different MPH aperture-layout designs, plus variations in projection multiplexing (MUX) and truncation, for a prototype brain-dedicated MPH SPECT system, named AdaptiSPECT-C, to understand tradeoffs for such choices and guide selection of an optimal design for construction of the actual AdaptiSPECT-C system.
Methods: The prototype AdaptiSPECT-C system investigated herein employs 25 MPH gamma-camera modules arranged in three rings to image a 21 cm diameter spherical volume-of-interest (VOI). With a focal point (FP) to center of detector distances of 38.7 cm, the pinhole aperture diameters were constrained to provide a calculated spatial resolution of 8 mm at the FP. Variations in the number of pinhole (PH) apertures, FP to aperture distance, PH layout, temporal changes in MUX, and extent-of-truncation of the projection images were investigated. Designs of the aperture layouts were used to create inputs for GATE and analytic simulations of a sphere phantom with uniform Tc-99 m activity filling the VOI, to assess MUX, detector utilization, and uniformity in reconstructed slices. We investigated axial and angular sampling using customized-spherical Defrise and Derenzo phantoms. Finally, we assessed reconstructed IQ and activity quantification in reconstructions of analytic simulations of the XCAT digital anthropomorphic phantom with activity and attenuation distributions mimicking clinical-SPECT brain-perfusion imaging. For each phantom, comparison was also made to imaging with a dual-headed SPECT system with low-energy high-resolution (LEHR) parallel-hole (Vertex high resolution [VXHR]) collimators.
Results: Sensitivity at the FP (SENS) for a Tc-99 m source in air calculated relative to a clinical dual-headed SPECT system with VXHR collimators was 2.7x higher for a single aperture with no MUX or truncation, increased to 5.7x for five apertures with limited VOI truncation and MUX, and decreased to 2.5x with 13 apertures with limited MUX. For the spherical tub phantom, limited truncation did not impact uniformity, MUX decreased it, and temporal shuttering of projections helped lessen this impact. Visually, the 6.4 mm rods were generally well differentiated for the single central apertures. For designs with four or more apertures, all the 4.8 mm rods were well differentiated visually. Projection images of the XCAT phantom acquired for an imaging time that would result in the minimum clinically recommended count-level for brain perfusion imaging with parallel-hole collimators, showed low MUX of the brain structures for all of the MPH aperture layout designs. The best reconstructions for the XCAT phantom, both visually and quantitatively, were obtained with the design using 4- or 5-PH-apertures for the aperture-layout design that included MUX and some truncation of imaging.
Conclusions: We determined for a prototype brain-dedicated MPH SPECT employing 25 camera modules in three rings with different PH layout designs imaging a 21 cm diameter spherical VOI, that a system with five apertures per module provided the best SENS, and IQ of the XCAT brain phantom, both visually and numerically.No embarg
Robot-assisted intrathalamic infusion for gene therapy in young children: surgical considerations
No full textObjective: Stereotactic gene therapy in children is challenging due to the fragility of the infant skull and long hours of infusion. The thalamus, an integrative hub for the entire cortex, has been shown to facilitate widespread gene/protein delivery via axonal transport. The aim of this study was to evaluate the safety and accuracy of bilateral thalamic convection-enhanced delivery (CED) of adeno-associated virus (AAV) vectors for GM2 gangliosidoses in children and to assess outcomes based on post-infusion imaging.
Methods: This clinical trial enrolled 10 pediatric patients, including 7 infants and toddlers and 3 children ranging in age from 5 to 12 years, who underwent bilateral thalamic rAAVrh8-HEXA/HEXB delivery via CED for GM2 gangliosidoses. The approximate trajectory entered the middle frontal gyrus, lateral to the frontal horn and caudate, passing through the anterior limb of the internal capsule to the thalamus. Injection volumes ranged from 180 μL to 1250 μL at a rate of 4 μL/min. The surgical technique for trajectory planning, cranial stabilization, operating room setup, stereotactic cannula placement, infusion parameters, and gene delivery was reviewed. The accuracy of catheter placement was calculated, and the volume of distribution (Vd) versus the volume of infusate (Vi) based on thalamic signal intensity on MRI was quantified.
Results: Ten children (age range 6 months to 12 years) with GM2 gangliosidosis were included. Twenty infusion cannulas were successfully placed for bilateral thalamic drug delivery. Intrathalamic cannula distance measurements ranged from 12.4 to 15.3 mm, and all the cannula steps were inside the thalamic boundaries to prevent backflow. There were no significant intraoperative complications. The mean targeting error was 1.3 ± 0.8 mm. The calculated volume of thalamic coverage by the infusate signal ranged from 5.9% to 53.3% (mean 26.9% ± 15.5%) in a dose escalating pattern. The Vd/Vi ratio ranged from 0.60 to 2.8 (mean 2.0 ± 0.6), depending on the infusate volume. The diffusate shape was circular to slightly ellipsoid in all patients.
Conclusions: In this study, the surgical technique used in the first in-human intrathalamic drug infusion gene therapy trial in young children with GM2 gangliosidosis was reviewed. The innovative stereotactic setup used robotic surgical assistance and ensured high-precision targeting and secure cannula placement during prolonged infusions, even in infants as young as 6 months of age. Post-infusion MRI confirmed that the infusate remained well contained within the thalamus. The mean Vd/Vi ratio of 2.0 is consistent with the literature. Overall, bilateral thalamic delivery of AAV transgene in children was safe and well tolerated.No embarg
Patterns of multimorbidity in older adults with multiple myeloma: An analysis of SEER-Medicare
No full textObjective: Multimorbidity influences the management of symptoms, treatment, and health outcomes for older adults with multiple myeloma. Our study characterized patient profiles defined by discrete chronic condition patterns and examined the distribution of their sociodemographic factors in older adults at time of diagnosis with multiple myeloma.
Methods: Using the Surveillance, Epidemiology and End Results (SEER) Program database linked with Medicare insurance claims (2007-2017), we examined 11,926 individuals diagnosed with multiple myeloma at age ≥ 65 years. Hierarchical cluster analysis was conducted to identify prevalent patterns of multimorbidity from thirty-three chronic conditions, and sociodemographic factors associated with the identified patterns were examined.
Results: The median age of the cohort was 77 years and 48% were women. Three patient groups with distinct patterns of multimorbidity were identified: minimal multimorbidity featuring minor burden of comorbid conditions (54.3%), psychiatric and musculoskeletal multimorbidity (21.5%), and a high multimorbidity group featuring cardiometabolic and multiple system disorders (20.7%). The remaining 3.5% did not have multimorbidity. Patients in the cardiometabolic and multisystem multimorbidity pattern were the oldest, more likely to reside in geographic areas with high poverty levels and comprised more men and Hispanic individuals than the other two patterns. The psychiatric and musculoskeletal multimorbidity pattern comprised the largest proportion of women and lowest proportion of non-Hispanic Black individuals. Those with relatively minimal multimorbidity burden were the most likely to be married.
Conclusions: Identifying patterns of multimorbidity in older adults newly diagnosed with multiple myeloma provides insight into the burden and clustering tendency of chronic conditions within similar patient groups. Our findings can inform tailored disease management and treatment programs that take these unique multimorbidity profiles into account.No embarg
Impact of COVID-19 Diagnosis on Weight Trajectories of Children in the US National COVID Cohort Collaborative [preprint]
Get PDFThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Background: The COVID-19 pandemic has exacerbated the obesity epidemic, with both adults and children demonstrating rapid weight gain during the pandemic. However, the impact of having a COVID-19 diagnosis on this trend is not known.
Methods: Using longitudinal data from January 2019 to June 2023 collected by the US National Institute for Health's National COVID Cohort Collaborative (N3C), children (age 2-18 years) with positive COVID-19 test results (n=11,474, 53% male, mean [SD] age 5.57 [±3.29] years, 54% white, mean [SD] 5.2 [±2.9] BMI observations per participants) were matched with COVID-19 negative children with identical demographic characteristics and similar observation window. We compared BMI percentile trajectories between the COVID-19 positive and COVID-19 negative cohorts, with further evaluation performed on COVID-19 positive patients stratified by hospitalization status.
Results: COVID-19 positive patients had a greater increase in %BMIp95
than COVID-19 negative patients (average increase of 2.34 (±7.73) compared to 1.46 (±6.09), p<0.0005). COVID-19 positive patients gained more weight after their diagnosis of COVID-19 than before. Non-hospitalized children gained more weight than hospitalized children (average increase in %BMIp95 of 2.38 (±7.65)) compared to 1.87 (±8.54)). Mixed effect regression analyses demonstrated that these associations remained even after adjusting for time, demographics, and baseline %BMIp95.
Conclusions: Having a COVID-19 diagnosis was associated with more rapid weight gain, especially after diagnosis and early in the pandemic. Future research should explore the reasons for this association and the implications for future health emergencies.The UMass Center for Clinical and Translational Science (UMCCTS), UL1TR001453, provided funding or data for this study.No embarg
Infliximab Pharmacokinetics, Dosing, and Response in Hospitalized Patients with COVID-19 Pneumonia: A Secondary Analysis of a Multinational Randomized Clinical Trial (ACTIV-1 IM)
No full textInfliximab may play an important role in reducing mortality in severe COVID-19, though optimal dosing is unknown. This secondary analysis of the ACTIV-1 IM trial characterized infliximab pharmacokinetics and outcomes in patients hospitalized with severe COVID-19. ACTIV-1 IM included patients admitted with COVID-19 pneumonia who received infliximab in addition to routine care. Infliximab was administered as a single 5-mg/kg intravenous dose. The primary exposure variable was predicted infliximab concentrations over 28 days (AUC). Logistic regression modeling was used to relate AUC to the primary outcome of 28-day mortality, adjusted for age. The relationship between AUC and the secondary outcome of time to recovery was evaluated using a Fine-Gray model, adjusted for age, with death as a competing risk. AUC was higher in patients who did not die versus those who died, with a median (range) of 20,681 mg h/L (8379-60,322) versus 17,392 (9543-43,145), P 17,400 mg h/L, albeit at a lower rate (1.18-fold higher [95% CI 1.07-1.32]), P < .002 for both. Overall, 113/390 (29.0%) patients did not achieve an optimal predicted infliximab AUC of at least 17,400 mg h/L, particularly those <100 kg and those with the highest baseline disease severity.The UMass Center for Clinical and Translational Science (UMCCTS), UL1TR001453, helped fund this study.No embarg
Metabolomic Signatures of Dietary Patterns and Incident Radiographic Knee Osteoarthritis: A Case-Cohort Study from Osteoarthritis Initiative
Get PDFOBJECTIVE: Dietary factors related to inflammation, obesity, and metabolism may contribute to OA development. This study examines the relationship between metabolomic signatures of dietary patterns and radiographic knee OA incidence.
METHODS: This case-cohort study included 603 participants from the Osteoarthritis Initiative, comprising 237 incident radiographic knee OA cases and 366 non-cases during a 6-year followup. Plasma metabolomes were analyzed using liquid chromatography-tandem mass spectrometry. We averaged metabolite levels at baseline and year 1 as the exposure and identified incident cases with those who had a Kellgren and Lawrence grade ≥2 in follow-ups. We selected 46 metabolites significantly associated with major food groups based on previous studies. Principal component analysis identified four metabolomic signatures related to specific food groups. Weighted logistic regression was used to examine associations between metabolomic signature scores and knee OA incidence.
RESULTS: Among the 603 participants, after adjusting for age, sex and other covariates the highest quartiles of two metabolomic signatures associated with healthy food groups were linked to a reduced OA risk compared to the lowest quartile [Odds ratio (95% CI): 0.69 (0.44, 1.08) and 0.61 (0.40, 0.92)]. However, after further adjustment for BMI, these associations weakened. The proportions of the associations mediated through BMI for these two signatures were 43.7% and 81.4%, respectively. The other signatures were null.
CONCLUSION: Metabolomic signatures of healthy dietary patterns may be linked to a lower risk of radiographic knee OA, with BMI potentially playing an intermediary role. Further studies are needed to explore causality.1 year2026/12/1
Investigating Functional Germline Helicase and Argonaute Interactions in C. elegans Germline
No full textIn the C. elegans germline, Argonautes and their small RNA (sRNA) cofactors localize within perinuclear nuage and regulate germline transcripts, yet how sRNAs are matched to the correct Argonaute remains unclear amid concurrent expression of ~20 Argonautes from all known clades and many sRNA classes. In addition, years of research have surmised that nuage, perinuclear domains rich with protein and RNA, are highly dynamic, yet contain ordered subdomains. I hypothesize that nuage forms spatially restricted subdomains that enable faithful Argonaute-sRNA sorting. Here I disrupt Argonaute loading and read out changes in localization and biochemical interactions to probe loading pathways.
Using this methodology, I uncover that nuclear Argonaute, WAGO-9, shuttles to Mutator foci, specialized subcompartments in nuage, enriched with factors that synthesize WAGO-class sRNA guides. Furthermore, I find one member of the Vasa family of germline helicase, GLH-1, itself capable of nucleating nuage domains, preferentially associates with an allele of WAGO-1, predicted to be unloaded WAGO-1, and possibly discriminates against other WAGO-class Argonautes.
Lastly, I find that this unloadable mutation of WAGO-1 also induces colocalization of GLH-4 and the PIWI Argonaute, PRG-1, within an enlarged nuage domain. Notably, this domain forms adjacent to intranuclear piRNA-cluster transcription sites, suggesting a spatial link. Molecular data support a model in which GLH-4 binds the 3’ ends of piRNA precursors to facilitate decapping, trimming, and subsequent loading onto PRG-1. Our findings suggest that active piRNA transcription directs the proximal formation of a specialized nuage domain, enriched with piRNA maturation factors. Taken together, we propose that nuage can simplify the complexity of Argonaute-sRNA sorting by partitioning Argonautes within subdomains enriched with the appropriate sRNA biogenesis factors.Interdisciplinary Graduate Program6 months2026-03-2
"Seipin mediates Perilipin-1 recruitment to lipid droplets to preserve human adipocyte identity" [preprint]
Get PDFThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Congenital generalized lipodystrophy type 2 (CGL2) is caused by mutations in the gene, which encodes the protein seipin. However, how seipin loss causes adipose tissue failure remains unclear. Using human adipocyte progenitor cells capable of robust differentiation in vitro and in vivo, we reveal two unexpected findings that redefine CGL2 pathogenesis. First, seipin is dispensable for lipid droplet biogenesis but essential for recruiting the major adipocyte scaffold protein Perilipin 1 (PLIN1) to the lipid droplet surface. Second, we discover that the integrity of the lipid droplet serves as an organelle to nucleus quality control checkpoint enforcing adipocyte identity. Without seipin-dependent PLIN1 recruitment, adipocytes exhibit enhanced lipolysis and ceramide accumulation, triggering an unexpected cellular response of de-differentiation into a progenitor-like state. From this de-differentiated state, cells can undergo additional cycles of differentiation and de-differentiation upon repeated adipogenic stimuli. However, some cells escape de-differentiation, instead forming a single large droplet and displaying severe cellular structural abnormalities. Consistent with this model, we find functional adipose tissue can form in vivo from seipin-deficient cells, yet ultimately fails. These findings resolve conflicting models of CGL2 pathogenesis by reframing seipin as a regulator of PLIN1 recruitment, rather than droplet formation per se, and reveal the fundamental role of lipid droplet integrity in the development of functional human adipocytes.No embarg
Per- and polyfluoroalkyl substances and hand osteoarthritis: data from the Osteoarthritis Initiative
Get PDFOBJECTIVE: To explore whether biological levels of specific per- and polyfluoroalkyl substances (PFAS) and a mixture of PFAS - reflecting the overall effect and accounting for correlations among each PFAS - relate to incident hand osteoarthritis (HOA) and progression.
METHODS: Among a case-cohort sample from the Osteoarthritis Initiative (n=1,878), we examined associations of 8 PFAS in serum with odds of developing over the subsequent 4 years (1) symptomatic HOA and (2) an increased number of joints with radiographic osteoarthritis (Kellgren-Lawrence≥2; yes/no). We used weighted logistic regression to assess single PFAS (continuous and quartiles) and quantile g-computation to assess the PFAS-mixture in relation to our primary outcomes.
RESULTS: Participants were primarily female (58%) and on average 62 years of age and overweight (mean BMI=28.6 kg/m). Participants with higher perfluorodecanoic acid (PFDA) and perfluorononanoic acid (PFNA; continuous variables) had greater odds of incident symptomatic HOA [OR (95%CI) per interquartile-range increment: PFDA 1.12 (1.05-1.20); PFNA 1.07 (1.00-1.13)], but associations were not monotonic when these PFAS were represented in quartiles. Participants with higher perfluorohexane sulfonoic acid (PFHxS) had lower odds of incident HOA [e.g., OR (95%CI): 0.94 (0.88-1.00) per interquartile-range increment]. We observed no other consistent associations between PFAS and either outcome.
CONCLUSION: We observed possible associations of PFDA and PFNA serum concentrations with symptomatic HOA incidence, but we otherwise found no consistent evidence that greater PFAS concentrations relate to a greater chance of developing HOA incidence or progression.1 year2026-12-2
Characterization of the Role of CD4 T Cell Help in Promoting Islet-specific CD8 T Cell Responses in Type 1 Diabetes Pathogenesis
Get PDFType 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by CD8+ T cell-mediated destruction of the insulin-producing beta cells within the pancreatic islets. Although CD8+ T cells are thought to be the primary mediators of beta cell killing, strong genetic associations with homozygous expression of MHC-II alleles bearing beta chain polymorphisms suggest a central role for CD4+ T cells in disease pathogenesis. Despite these recognized associations, the mechanisms by which heterozygous expression of one high-risk and one protective allele abrogates disease risk remain unclear. Here, using the non-obese diabetic (NOD) mouse model, we demonstrate that heterozygous expression of the T1D-protective I-Ag7 Beta-56P/57D allele induces negative selection to the I-Ag7-restricted T cell repertoire, including high-affinity beta-islet-specific CD4+ T cells, resulting in a marked reduction in the islet-specific CD8+ T cell response. Further, we show that protected mice exhibit a dramatic loss of CXCR6+ islet-specific CD4+ T cells, specifically implicating a role for this population in supporting islet-directed CD8+ T cell responses. Finally, we characterize the functional contribution of CD4+ T cell help in promoting CD8+ T cell effector differentiation in the periphery using NOD mouse models with genetically limited CD4+ T cell help. We find that islet-specific CD8+ T cells receiving inadequate help signals undergo increased levels of apoptosis, but can be rescued with IL-2 complex treatment. Taken together, these studies provide mechanistic insights into how protective MHC-II molecules manifest T cell tolerance and reveal how CD4+ T cell help contributes to the expansion and survival of islet-specific CD8+ T cells.Immunology and Microbiology6 months2026-01-3